BRAF Mutation Less Common Among Patients With Melanoma in Ireland

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Data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10 reveals that the BRAF mutation was found to occur at a significantly lower frequency in patients with melanoma in Ireland.

BRAF Mutation Less Common Among Patients With Melanoma in Ireland

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The study, which included two independent cohorts of patients in Europe, revealed that only about 20 percent of a cohort of Irish patients with melanoma harbored a BRAF mutation.

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"The clinical approval of a BRAF inhibitor that blocks the function of the mutant BRAF protein is currently one of the most promising approaches to treat metastatic melanoma," said William M. Gallagher, Ph.D., associate professor of cancer biology at the UCD Conway Institute in Dublin, Ireland. "The observation of a reduced BRAF mutation rate in Irish patients directly influences future treatment strategies for these patients."

Gallagher and colleagues investigated cancer-related changes in 33 genes known to be of key importance in cancer development. They evaluated two independent cohorts of patients with melanoma, including 94 patients from Ireland and 60 patients from Belgium.

Researchers found that 21 percent of patients with melanoma from Ireland had a BRAF mutation compared with 52 percent of the Belgian patients.

The currently approved BRAF inhibitor specifically targets the BRAFV600E mutation; therefore, the researchers also analyzed the percentage of patients carrying this specific BRAF mutation. They found that 19 percent of the Irish patients had the BRAFV600E mutation compared with 43 percent of the Belgian patients. They found similar results after analyzing tumor tissue from three additional independent cohorts of patients with melanoma from Ireland. In these three groups of 137 patients, 79 patients and 34 patients, the researchers found the BRAFV600E mutation in 21 percent, 20 percent and 32 percent of patients, respectively.

"Treatment with the clinically approved BRAF inhibitor that blocks the function of the mutant BRAF protein will only be applicable to patients who possess the relevant BRAFV600E mutation," Gallagher said. "As a result, the majority of Irish patients with melanoma will not benefit from this therapy and are currently left without good alternative treatment possibilities."

Although the exact reason for this difference is unknown, Gallagher offered some explanations. First, it is known that BRAF and NRAS mutations are mutually exclusive, and he and his colleagues found a higher rate of NRAS mutations among the Irish patients compared with the patients from Belgium (21 percent versus 13 percent).

In addition, 12 percent of Irish patients had a mutation in the c-MET gene; none of the Belgian patients did. A mutation in c-MET has rarely been found in melanoma before, according to Gallagher.

"This study shows that the molecular biology underlying melanoma can change in different demographic areas," Gallagher said. "Hence, to be able to give patients the best possible treatment, we need to take into account the molecular variations, or genomic landscape, contributing to tumor development and progression between different populations."

About the American Association for Cancer ResearchFounded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit AACR.org.

Background: Aberrant activity of the mitogen-activated protein kinase (MAPK) signalling pathway represents a critical factor in the initiation and development of melanoma. Activation can be the result of largely mutually exclusive somatic mutations of KIT, NRAS, or more frequently, BRAF (V600E). The FDA and EMA approval of a BRAF inhibitor (vemurafenib) that blocks the function of the BRAFV600E protein established a new paradigm for targeted drug development. Currently, BRAF inhibitors are one of the most promising approaches to treat metastatic melanoma.

Methods: In this study, we applied mass spectrometry-based SNP genotyping Sequenom) to detect single nucleotide mutations in 33 cancer-related genes including BRAF, NRAS, KIT, CTNNB1, GNAS, and MET. PCR and extension primers for the multiplexed assay were designed with the Sequenom Assay Design software. Samples were processed as recommended by the manufacturer. Matrix chips were assayed on a Sequenom MassArray MALDI-TOF Mass Array system. Visual inspection and Sequenom Typer software were used to perform genotyping based on mass spectra. We compared two independent melanoma cohorts, one from Ireland (SVUH cohort; n=97) and the other from Belgium (Leuven cohort; n=60).

Results: Intriguingly, patients from Ireland showed significant lower BRAFV600E mutation rates (19.0%) when compared to the mutation frequency seen with the Belgian cohort (43.3%) or with the mutation frequency reported by other studies on non-Irish populations (50-70%). In addition, BRAFV600K mutation is rare in the SVUH cohort (1.0%) compared with the Leuven cohort (6.7%). Mutations in BRAFV600M and V600R were <2% in both groups. Although the number of NRASQ61 mutant cases was slightly higher among the Irish melanoma patients compared with Belgium patients (20.6% and 13.3%, respectively), this does not fully account for the difference in RAFV600E mutation rate. In contrast, many BRAFV600 WT patients in the SVUH cohort carried significantly increased mutation rates in MET (11.4%) compared to the Leuven cohort (0%) and reported elsewhere (2%). c-MET is a receptor tyrosine kinase that activates multiple signal transduction pathways, including MAPK, PI3K, WNT, and Notch. MET inhibitors that are currently in clinical trials include cabozantinib and foretinib and might be a valuable alternative treatment strategy for patients exhibiting this mutation. Mutation rates of the other examined genes were always <5% and did not significantly differ between the groups.

Conclusion: Our observation of reduced BRAFV600E mutation rates in Irish patients will directly impact future treatment strategies for these patients. The identification of substantial mutation rates in MET opens up opportunities for targeting a significant subset of melanoma patients with MET inhibitors.

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